The term "crown ether compound" in this specification and in the attached claims is used in the widest meaning of the term, viz. as comprising not only coronand compounds, but also podand compounds and cryptand compounds.
A description of coronand, podand and cryptand compounds may be found in Merck-Schuchardts publication: E. Weber "Phase Transfer Catalysts" and in the literature cited or referred to therein:
A further description of these types of compounds may be found in the following articles, all having the title: "Progress in Crown Ether Chemistry": F. Vogtle, E. Weber and U. Elben, Kontakte 2, (1980), page 36 ff; E. Weber and F. Vogtle, Kontakte 1 (1981), page 24 ff; E. Weber, Kontakte 1 (1982), page 24 ff; Kontakte 1 (1983), page 38 ff; as well as Kontakte 1 (1984), page 26 ff.
Said literature is incorporated herein by reference.
The crown ether compounds first synthesized were of the type 18-crown-6, meaning they comprised the following ring: ##STR1## but since then other compounds of this type have been prepared some of which having a greater amount of hetero atoms while ethers having a smaller amount of hetero atoms.
The term "coronands" comprises also compounds of this type in which the oxygen atoms have been completely or partly replaced by sulphur, nitrogen or phosphor atoms. The term further comprises such compounds in which groups of various composition and structure have been substituted on or condensed to the ring.
The term cryptand is used to cover corresponding compounds having bi- or polycyclic ring systems having arbitrary hereto atoms, while podand compounds are open chained coronand/cryptand analogs.
It has been suggested reserving the term "crown ether" to designate coronand compounds in which all hetero atoms are oxygen, but in the present specification and the attached claims the term crown ether is used, as already mentioned, in the common broad sense, meaning covering all coronand, podand and cryptand compounds.
Several applications have been suggested for crown ether compounds.
Most of these suggested applications have been based on the fact that, dependent on the characteristics of the individual compounds, such as dimensions of rings and cavities, the compounds are able to bind, often with high selectivity, not only cations but also anions and non-charged organic molecules. Several of these suggested applications have been related to the exploitation of the compounds in chemical syntheses where they may have a catalytic effect. In connection with such applications it has been suggested immobilizing the crown ether compounds by attaching them to polymer resins especially polystyrene, with the view of minimizing the consumption of relatively expensive crown ether compounds.
Also several other applications within the technical field have been suggested.
Besides, it has been reported that benzo-crown-ethers such as benzo-15-crown-5-derivatives and dibenzo-30-crown-10 have an anti-coccocidal activity in tissue culture tests (George R. Brown and Allan J. Foubister: J. Med. Chem. 1983, 26, 590-592). However, no in vivo effect was demonstrated when the compounds were fed to poultry admixed in the fodder.
Also U.S. Pat. No. 3,997,565 discloses that certain crown ethers in vitro snow antivial effect, for which reason the compounds have been suggested inter alia as disinfectants. No therapeutic use is mentioned in said patent specification.
In the first of the above cited articles E. Weber states that the anti-bacterial and anti-viral effect of certain crown ether compounds is due to their ability of complexing metals, but at the same location it is stated that real application in the physiological-pharmacological field is still out of the range.
Hungarian patent specification No. 187 360 discloses a process for producing certain cyclodextrin-crown ether derivatives. It is stated that if the cyclodextrin molecule and the crown ether molecule are attached together through a side-chain containing amino or carbonyl groups, the resulting molecule may be able to complex saltlike organic compounds since a complex bond is formed both with the cation and the apolar group of the organic anion. It is asserted that this complex formation can be utilized for amending pharmacocinematic characteristics of organic molecules having ionic bond. There is no suggestion that the cyclodextrin-crown ether derivatives as such should be applicable as pharmaceuticals and nothing seems to be mentioned as to their compatibility within the human body.
The specification of WO-publication number 89/01476 deals with special crown ether compounds, namely tetra-aza compounds and metal complexes thereof as well as the use therof for diagnostic purposes or for obtaining a cytotoxic action, preferably after complexing with radioactive atoms. The possibility of connecting these crown ethers to other molecules such as proteins, especially antibodies, peptides or carbonhydrates is mentioned as a theoretical, non-substantiated possibility. It is not indicated what advantages could be expected by such purely hypothetical attachment, apart from the case where said attachment is to an antibody. Since the only therapeutical activity mentioned is a cytotoxic effect it is, on the basis of the explanation given below, obvious that an attachment to carbohydrates only comes into consideration with low molecular weight carbohydrates. A product obtained by attachment to for example polysaccharides has actually no or only a small cytotoxic activity per so.
The reason why crown ethers have not yet found medical or therapeutic application is that free crown ethers as such are extremely toxic towards mammals and humans.
It has now turned out that the toxicity of crown ethers is drastically diminished when they are attached to a polysaccharide, whereas their, sometimes very specific, ability of binding cations, anions or non-charged molecules is maintained.
It has further turned out that it is possible to produce crown ether-polysaccharide condensation products which can be administered intraveneously or which extracorporally can be contacted with a stream of blood without the risk that bound crown ether compounds be liberated as toxic, free crown ether compounds.